Project Summary: Memory loss associated with aging and Alzheimer's disease is a leading threat to independence, costing families and healthcare providers millions of dollars per year. Memory loss is most noticeable when episodes overlap, for example, in recalling where one's car was parked from one day to the next. This ability requires the hippocampus, a brain structure positioned to compare multi-sensory inputs of current, novel experience with stored representations of prior experience. It is well-established that aging decreases novelty sensitivity, but how this relates to hippocampal-dependent memory loss has not yet been explicitly investigated. The monoamine neurotransmitter dopamine (DA) provides a robust novelty signal to the entire brain, yet only a few studies to date have linked DA to hippocampal novelty detection, and age-associated changes in DA circuits, outside the context of Parkinson's disease and movement disorders, remain for the most part unexplored. The long-term goal of this research is, therefore, to determine how brain-wide neural activity, coordinated by monoamine neurotransmitters (including dopamine) permits memory, and how monoaminergic modulation can be harnessed to promote cognitive resilience in individuals at risk for memory loss, dementia and Alzheimer's disease. Relevant to this goal, we have validated a rodent target-lure discrimination task that parallels mnemonic similarity tasks used to detect early signs of cognitive decline in human aging and Alzheimer's disease. In preliminary studies, we found hippocampal neural activity is required for accurate discrimination of a known target object from novel lure objects, and that blockade of hippocampal D1/D5 dopamine receptors specifically impairs discrimination of a known target from similar, novel lures, which recapitulates deficits observed in aged rats. This proposal will test the central hypothesis that the aged hippocampus becomes desensitized to novelty, resulting in a reduced ability to resolve new input from similar existing representations, but that increasing dopamine signaling could restore sensitivity to novel information. Studies in the K99 phase will determine neurophysiological signatures of trial-specific rapid novelty detection in the hippocampus and its modulation by dopamine in young adult rats. High-channel count in vivo physiological recordings, pharmacology, and optogenetic stimulation of DAergic inputs to the hippocampus will be combined with an automated touchscreen discrimination task to attain this aim. Studies in the R00 phase will determine if aging attenuates hippocampal neurophysiological responses to novelty, and if these neurophysiological responses and stimulus discrimination accuracy can be restored by increasing DA receptor signaling. Completing the proposed research will unite existing literatures on hippocampal-dependent memory loss in aging with those on rapid novelty signaling by DA. Establishing this relationship is expected to open entirely new avenues of treatment for memory problems that threaten independence in aging and Alzheimer's disease.